Small-diameter sensory neurons that sense pain are classified as nociceptors. During embryonic development virtually all nociceptors express TrkA, the receptor for the neurotrophic factor NGF, and depend on NGF for survival. During late embryonic and early postnatal life, small-diameter unmyelinated nociceptors (C-fiber nociceptors) diverge into two distinct subpopulations of roughly equal number. One population continues to express TrkA. The other population down-regulates TrkA expression and expresses Ret, the receptor for the neurotrophic factors belonging to the GDNF family. In addition to trophic factor receptor expression, these two subpopulations of C-fiber nociceptors can be distinguished based on peptide expression, their ability to bind the plant lectin, isolectin B4 (IB4), and the pattern of their central and peripheral projections. Nociceptors that express TrkA also express the peptides CGRP and substance P, do not bind IB4, and project to lamina I and IIo of the dorsal horn. Nociceptors that express Ret do not typically express these neuropeptides, do bind the lectin IB4, and project to LIIi of the dorsal horn. Evidence suggests that neurotrophic factor signaling modulates structural and functional properties of sensory neurons in the postnatal period and in maturity. Perinatal death of Ret-null mice because of kidney agenesis has limited the study of Ret function in postnatal and mature sensory neurons. To overcome this limitation, we have created a mouse in which Ret is deleted exclusively in IB4-positive nociceptors by crossing a mouse with floxed Ret alleles (Ret-conditional mouse) with a mouse expressing Cre recombinase under a nociceptor specific promoter (the sodium channel a subunit 1.8 promoter). We will use anatomical and behavioral methods to determine the effect of Ret deletion on the structure and function of IB4 nociceptors in this mouse. Analysis of this mouse will enable us to determine the role of Ret signaling in nociceptive sensory-neuron survival and in the maintenance of nociceptor structure and function. In addition, this mouse may provide insights into the specific contribution of the IB4 subpopulation of nociceptors to pain transduction. The treatment of chronic pain is a major unmet medical need. We have created a novel mouse in which Ret, the receptor for the GDNF family neurotrophic factor ligands (GFLs) is deleted in nociceptors (neurons that sense pain). This novel mouse will allow us to determine the role of the GFLs in nociceptor survival and function and to study mechanisms by which GFLs are effective in the treatment of chronic pain syndromes.